We propose to determine the epigenetic contribution to depression, the most common debilitating psychiatric disorder, through a highly focused approach that combines cutting-edge epigenomic analysis with a stress-based mouse model of the illness. Stress is known to play a major role in triggering major depressive disorder (MDD), likely through interaction with genetic vulnerability factors. Recent work showing stress-mediated epigenetic control of BDNF, a gene that plays a key role in depression and antidepressant response, provides molecular evidence that epigenetic mechanisms can mediate this interaction. Additional recent work from a Co- Investigator at Johns Hopkins shows that DNA demethylation of genes including Bdnf plays a role in neural plasticity and neurogenesis in response to electroconvulsive stimulation. These results suggest the possibility that new insights into the etiology and pathophysiology of depression, and into the mechanisms of treatment response, can be gleaned from a genome- wide epigenetic approach to the study of stress-induced, and medication reversed, changes in rodent brain DNA. The tools to perform genome-wide epigenetic studies have only just become available and our Epigenetics Center at Johns Hopkins has been a leader in the development of such tools, having created the Comprehensive Hybridization Arrays for Relative Methylation (CHARM) method for genome-wide DNA methylation (DNAm) studies. In addition to our epigenomics expertise, our team also has expertise in the other facets of this project that are crucial to its success, including rodent models of stress, the genetics of depression, and neurobiology. We intend to test the following specific aims: 1) determine the behavioral and endocrine outcomes of chronic social stress and their persistence or reversibility by antidepressant drug treatment; 2) test whether social stress results in depressive-like behaviors through epigenetic modifications; and 3) validate and extend top DNAm difference findings through study of gene expression, DNAm in other brain regions, DNAm in blood, and histone modifications in genes.